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Friday, July 9, 2010

HIV research is undergoing a renaissance that could lead to new ways to develop vaccines against the AIDS virus and other viral diseases.

In the latest development, U.S. government scientists say they have discovered three powerful antibodies, the strongest of which neutralizes 91% of HIV strains, more than any AIDS antibody yet discovered. They are now deploying the technique used to find those antibodies to identify antibodies to influenza viruses.

Mark Schoofs discusses a significant step toward an AIDS vaccine, U.S. government scientists have discovered three powerful antibodies, the strongest of which neutralizes 91% of HIV strains, more than any AIDS antibody yet discovered.

The HIV antibodies were discovered in the cells of a 60-year-old African-American gay man, known in the scientific literature as Donor 45, whose body made the antibodies naturally. The trick for scientists now is to develop a vaccine or other methods to make anyone's body produce them as well.

That effort "will require work," said Gary Nabel, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, who was a leader of the research. "We're going to be at this for a while" before any benefit is seen in the clinic, he said.

The research was published Thursday in two papers in the online edition of the journal Science, 10 days before the opening of a large International AIDS Conference in Vienna, where prevention science is expected to take center stage. More than 33 million people were living with HIV at the end of 2008, and about 2.7 million contracted the virus that year, according to United Nations estimates.

Vaccines, which are believed to work by activating the body's ability to produce antibodies, eliminated or curtailed smallpox, polio and other feared viral diseases, so they have been the holy grail of AIDS research.

The Quest for a Vaccine

Last year, following a trial in Thailand, results of the first HIV vaccine to show any efficacy were announced. But that vaccine reduced the chances of infection only by about 30%, and controversy erupted because in one common analysis the results weren't statistically significant. That vaccine wasn't designed to elicit the new antibodies.

The new discovery is part of what Wayne Koff, head of research and development at the nonprofit International AIDS Vaccine Initiative, calls a "renaissance" in HIV vaccine research.

Antibodies that are utterly ineffective, or that disable just one or two HIV strains, are common. Until last year, only a handful of "broadly neutralizing antibodies," those that efficiently disable a large swath of HIV strains, had been discovered. And none of them neutralized more than about 40% of known HIV variants.

But in the past year, thanks to efficient new detection methods, at least a half dozen broadly neutralizing antibodies, including the three latest ones, have been identified in peer-reviewed journals. Dennis Burton of the Scripps Institute in La Jolla, Calif., led a team that discovered two broadly neutralizing antibodies last year; he says his team has identified additional, unpublished ones. Most of the new antibodies are more potent, able to knock out HIV at far lower concentrations than their previously known counterparts.

HIV is a highly mutable virus, but one place where the virus doesn't mutate much is where it attaches to a particular molecule on the surface of cells it infects. Building on previous research, researchers created a probe, shaped exactly like that critical site, and used it to attract only those antibodies that efficiently attack it. That is how they fished out of Donor 45 the special antibodies: They screened 25 million of his cells to find 12 that produced the antibodies.

Donor 45's antibodies didn't protect him from contracting HIV. That is likely because the virus had already taken hold before his body produced the antibodies. He is still alive, and when his blood was drawn, he had been living with HIV for 20 years.

While he has produced the most powerful HIV antibody yet discovered, researchers say they don't know of anything special about his genes that would make him unique. They expect that most people would be capable of producing the antibodies, if scientists could find the right way to stimulate their production.

Dr. Nabel said his team is applying the new technique to the influenza virus. Like HIV, influenza is a highly mutable virus—the reason a new vaccine is required every year.

"We want to go after a universal vaccine" by using the new technique to find antibodies to a "component of the influenza virus that doesn't change," said NIAID director Anthony Fauci. In principle, Dr. Fauci said, the technique could be used for any viral disease and possibly even for cancer vaccines.

Some of the new HIV antibodies discovered over the past year attack different points on the virus, raising hopes that they could work synergistically.

In unpublished research, John Mascola, deputy director of the Vaccine Research Center, has shown that one of Dr. Burton's antibodies neutralizes virtually all the strains that are resistant to the antibody from Donor 45. He also found the reverse: The antibody from Donor 45 disables HIV strains resistant to one of Dr. Burton's best antibodies. Only one strain out of 95 tested was resistant to both antibodies, he said. Dr. Mascola is one of the authors of Thursday's papers.

Researchers say they plan to test the new antibodies, likely blended together in a potent cocktail, in three broad ways.

First, the antibodies could be given to people in their raw form, somewhat like a drug, to prevent transmission of the virus. But they would likely be expensive and last in the body for a limited time, perhaps weeks, making that method impractical for all but specialized cases, such as to prevent mother-to-child transmission in childbirth.

The antibodies could also be tested in a "microbicide," a gel that women or gay men could apply before sex to prevent infection.

The antibodies might even be tried as a treatment for people already infected. While the antibodies are unlikely to completely suppress HIV on their own, say scientists, they might boost the efficacy of current antiretroviral drugs.

Dr. Nabel said that the Vaccine Research Center has contracted with a company to produce an antibody suitable for use in humans so that testing in people could begin.

A second way to use the new research is to stimulate the immune system to produce the antibodies. Jonas Salk injected people with a whole killed polio virus, and virtually everyone's immune system easily made antibodies that disabled the polio virus. But for HIV, the vast majority of antibodies are ineffective. Now, scientists know the exact antibodies that must be made—those found in Donor 45 and in Dr. Burton's lab, for example. So researchers need "a reverse engineering technology" to find a way to get everyone to produce them, said Greg Poland, director of vaccine research at Mayo Clinic in Rochester, Minn.

That's what scientists at Merck & Co. have done. In a study published this year in the Proceedings of the National Academy of Sciences, the Merck Scientists knew that an old antibody, weaker than the newly discovered ones, attaches to a particularly vulnerable part of HIV. They created a replica of that piece of the virus to train the immune system to produce antibodies aimed at that exact spot. It was a painstaking process, requiring researchers to add chemical bonds to stabilize the replica so that it wouldn't collapse and lose its shape. Eventually, Merck was able to make experimental vaccine candidates capable of spurring guinea pigs and rabbits to produce antibodies that home in on the target site and neutralize HIV. Those vaccines weren't nearly powerful enough, but, said Dr. Koff, Merck's research provides a "proof of principle" that reverse engineering can work for the much stronger new antibodies.

There are other potential pitfalls. There is evidence that Donor 45's cells took months or possibly even years to create the powerful antibodies. That means scientists might have to give repeated booster shots or devise other ways to speed up this process.

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Finally, there are experimental methods that employ tactics such as gene therapy. Nobel laureate David Baltimore is working on one such approach.

His team at the California Institute of Technology in Pasadena, Calif., has stitched genes that code for antibodies into a harmless virus, which they then inject into mice. The virus infects mouse cells, turning them into factories that produce the antibodies.

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